Pharmaceutical composition

ABSTRACT

Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of Ser. No. 11/523,771, filed Sep.20, 2006, which is a continuation of Ser. No. 10/937,494, filed Sep. 10,2004, now U.S. Pat. No. 7,144,900, which is a divisional of Ser. No.10/462,793 filed Jun. 17, 2003, now U.S. Pat. No. 6,911,459, which is adivisional of Ser. No. 10/095,453 filed Mar. 13, 2002, now U.S. Pat. No.6,599,923, which is a divisional of Ser. No. 09/973,689, filed Oct. 11,2001, now U.S. Pat. No. 6,384,062, which is a divisional of Ser. No.09/453,521 filed Dec. 3, 1999, now U.S. Pat. No. 6,329,404, which is adivisional of Ser. No. 09/280,710 filed Mar. 30, 1999, now U.S. Pat. No.6,150,383, which is a divisional of Ser. No. 09/057,465 filed Apr. 9,1998, now U.S. Pat. No. 5,965,584, which is a divisional of applicationSer. No. 08/667,979 filed Jun. 19, 1996, now U.S. Pat. No. 5,952,356.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisingan insulin sensitivity enhancer in combination with one or more otherantidiabetics differing from said enhancer in the mechanism of action.

BACKGROUND OF THE INVENTION

In recent years, the pathology of diabetes has become more wellunderstood and, in parallel, drugs specific for the respectivepathologic states have been developed. Accordingly, a variety of drugshaving new mechanisms of action have appeared one after another.

Insulin sensitivity enhancers are also known as insulin resistancedeblockers because they have the action of normalizing the impairedinsulin receptor function, and are gathering much attention in theseyears.

Regarding such insulin sensitivity enhancers, a very useful compoundsuch as pioglitazone has been developed [Fujita et al., Diabetes, 32,804-810, 1983, JP-A S55 (1980)-22636 (EP-A 8203), JP-A S61 (1986)-267580(EP-A 193256)]. Pioglitazone restores the impaired insulin receptorfunction to normalize the uneven distribution of glucose transporters incells, the cardinal enzyme systems associated with glycometabolism, suchas glucokinase, and enzyme systems associated with lipidmetabolism, suchas lipoprotein lipase. As a result, insulin resistance is deblocked toimprove glucose tolerance, and lower the plasma concentrations ofneutral lipids and free fatty acids. Since these actions of pioglitazoneare comparatively gradual and the risk of side effects in long-termadministration is also low, this compound is useful for obese patientswho are presumed to be highly insulin-resistant.

Also, insulin sensitivity enhancers such as CS-045, thazolidinedionederivatives and substituted thiazolidinedione derivatives are reportedto be used in combination with insulin [JP-A H4 (1992)-66579, JP-A H4(1992)-69383, JP-A H5 (1993)-202042]. However, the pharmaceuticalcomposition having a specific combination of the present invention isunknown.

Diabetes is a chronic disease with diverse pathologic manifestations andis accompanied by lipidmetabolism disorders and circulatory disorders aswell as glycometabolism disorders. As a result, diabetes tends toprogress involving various complications in many cases. Therefore, it isnecessary to select the drug of choice for the prevailing disease statein each individual case. However, this selection is often difficult inclinical settings because single use of each individual drug can notbring sufficient effects in some disease states and there are variousproblems such as side effect which is caused by an increased dose or along-term administration.

SUMMARY OF THE INVENTION

In view of the above state of the art, the inventors of the presentinvention did much research to develop antidiabetics which would notvirtually cause adverse reactions even on long-term administration andcould be effective for a large cohort of the diabetic population. As aconsequence, they discovered that the above object can be accomplishedby using an insulin sensitivity enhancer, such as the drug describedabove, in combination with other antidiabetics differing from saidenhancer in the mechanism of action, and accordingly have perfected thepresent invention.

The present invention, therefore, relates to:

1) A pharmaceutical composition which comprises an insulin sensitivityenhancer in combination with at least one member of the group consistingof an α-glucosidase inhibitor, an aldose reductase inhibitor, abiguanide, a statin compound, a squalene synthesis inhibitor, a fibratecompound, a LDL catabolism enhancer and an angiotensin converting enzymeinhibitor.

2) A pharmaceutical composition according to 1), wherein the insulinsensitivity enhancer is a compound represented by the formula:

wherein R represents an optionally substituted hydrocarbon orheterocyclic group; Y represents a group represented by —CO—, —CH(OH)—or —NR³— (wherein R³ represents an optionally substituted alkyl group);m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bondor a C₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atomor sulfur atom; R¹ represents hydrogen atom or an alkyl group; ring Emay optionally have 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to-form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; or a pharmacologically acceptable salt thereof.

3) A pharmaceutical composition according to 2), wherein the compoundrepresented by the formula (I) is pioglitazone.

4) A pharmaceutical composition according to 1), which comprises aninsulin sensitivity enhancer in combination with an α-glucosidaseinhibitor;

5) A pharmaceutical composition according to 4), wherein theα-glucosidase inhibitor is voglibose.

6) A pharmaceutical composition according to 4), wherein the insulinsensitivity enhancer is pioglitazone and the α-glucosidase inhibitor isvoglibose;

7) A pharmaceutical composition according to 1), which is forprophylaxis or treatment of diabetes.

8) A pharmaceutical composition which comprises a compound representedby the formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocyclic group; Y represents a group represented by —CO—, —CH(OH)—or —NR³— (wherein R³ represents an optionally substituted alkyl group);m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bondor a C₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atomor sulfur atom; R¹ represents hydrogen, atom or an alkyl group; ring Emay optionally have 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; with a proviso that R¹ does not representbenzopyranyl group when m and n are O, X represents CH, A represents abond, Q represents sulfur atom, R¹, L and M represent hydrogen atom andring E does not have further substituents; or pharmacologicallyacceptable salt thereof in combination with an insulin secretionenhancer and/or an insulin preparation.

9) A pharmaceutical composition according to 8), wherein the compoundrepresented by the formula (II) is the compound represented by theformula:

10) A pharmaceutical composition according to 8), wherein the compoundrepresented by the formula (II) is pioglitazone.

11) A pharmaceutical composition according to 8), wherein the insulinsecretion enhancer is glibenclamide.

12) A pharmaceutical composition according to 8), wherein the compoundrepresented by the formula (II) is pioglitazone and the insulinsecretion enhancer is glibenclamide.

13) A pharmaceutical composition according to 8), which is forprophylaxis or treatment of diabetes.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The term “insulin sensitivity enhancer” as used in this specificationmeans any and all drug substances that restore the impaired insulinreceptor function to deblock insulin resistance and consequently enhanceinsulin sensitivity. As examples of the insulin sensitivity enhancer,the compound represented by the formula (I) or a pharmacologicallyacceptable salt thereof can be mentioned.

In the formula (I), as the hydrocarbon group in the optionallysubstituted hydrocarbon group represented by R, mention is made ofaliphatic hydrocarbon groups, alicyclic hydrocarbon groups,alicyclic-aliphatic hydrocarbon groups, aromatic aliphatic hydrocarbongroups and, aromatic hydrocarbon groups. Number of carbon atoms in thesehydrocarbon groups is preferably 1 to 14.

The aliphatic hydrocarbon groups are preferably those having 1 to 8carbon atoms. As the aliphatic hydrocarbon groups, mention is made ofC₁₋₈ saturated-aliphatic hydrocarbon groups (e.g. alkyl group) asexemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl,isohexyl, heptyl and octyl, and C₂₋₈ unsaturated aliphatic hydrocarbongroups (e.g. alkenyl group, alkadienyl group, alkynyl group, alkadiynylgroup) as exemplified by vinyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl,2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl,1-heptynyl and 1-octynyl.

The alicyclic hydrocarbon groups are preferably those having 3 to 7carbon atoms. As the alicyclic hydrocarbon groups, mention is made ofC₃₋₇ saturated alicyclic hydrocarbon groups (e.g. cycloalkyl group) asexemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl, and C₅₋₇ unsaturated alicyclic hydrocarbon groups (e.g.cycloalkenyl group, cycloalkadienyl group) as exemplified by1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl,2-cyclohexenyl, 3-cyclohexeny, 1-cycloheptenyl, 2-cycloheptenyl,3-cycloheptenyl and 2,4-cycloheptadienyl.

As the alicyclic-aliphatic hydrocarbon groups, mention is made of, amongthose formed by combination of the above-mentioned alicyclic hydrocarbongroups with aliphatic hydrocarbon groups (e.g. cycloalkyl-alkyl group,cycloalkenyl-alkyl group), ones having 4 to 9 carbon atoms asexemplified by cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl,cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl,cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl andcycloheptylethyl.

The aromatic aliphatic hydrocarbon groups are preferably those having 7to 13 carbon atoms (e.g. aralkyl group). As the aromatic aliphatichydrocarbon groups, mention is made of C₇₋₉ phenylalkyl as exemplifiedby benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and1-phenylpropyl, and C₁₁₋₁₃ naphthylalkyl as exemplified byα-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl and α-naphthylethyl.

As the aromatic hydrocarbon groups, mention is made of, ones having 6 to14 carbon atoms as exemplified by phenyl, naphthyl (α-naphtyl,β-naphthyl).

In the formula (I), as the heterocyclic group in the optionallysubstituted heterocyclic group represented by R, mention is made of, forexample, 5- to 7-membered heterocyclic groups containing, as a ringcomponent atom, 1 to 4 hetero atoms selected from oxygen atom, sulfuratom and nitrogen atom, and a condensed ring group. As the condensedring, mention is made of, for example, these 5- to 7-memberedheterocyclic groups condensed with 6-membered ring containing one or twonitrogen atoms, benzene ring or 5-membered ring containing one sulfuratom.

Examples of these heterocyclic groups include 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl,benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl,1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl,1H-imidazo[4,5-b]pyridine-2-yl, 1H-imidazo[4,5-c]pyridine-2-yl,1H-imidazo[4,5-b]pyrazin-2-yl and benzopyranyl. Among them, pyridyl,oxazolyl or thiazolyl group is preferable.

In the formula (I), the hydrocarbon group and heterocyclic grouprepresented by R may optionally have 1 to 5, preferably 1 to 3substituents at any substitutable positions. Examples of suchsubstituents include aliphatic hydrocarbon group, alicyclic hydrocarbongroup, aryl group, aromatic heterocyclic group, non-aromaticheterocyclic group, halogen atom, nitro group, optionally substitutedamino group, optionally substituted acyl group, optionally substitutedhydroxyl group, optionally substituted thiol group, optionallyesterified carboxyl group, amidino group, carbamoyl group, sulfamoylgroup, sulfo group, cyano group, azido group and nitroso group.

Examples of the aliphatic hydrocarbon groups include C₁₋₁₅straight-chain or branched aliphatic hydrocarbon groups as exemplifiedby alkyl group, alkenyl group, and alkynyl group.

Preferable examples of the alkyl group include C₁₋₁₀ alkyl groups suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl,t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, -3,3-dimethylbutyl,2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.

Preferable examples of the alkenyl group include C₂₋₁₀ alkenyl groupssuch as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

Preferable examples of the alkynyl group include C₂₋₁₀ alkynyl groupssuch as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

As the alicyclic hydrocarbon group, mention is made of C₃₋₁₂ saturatedor unsaturated alicyclic hydrocarbon groups as exemplified by cycloalkylgroup, cycloalkenyl group and cycloalkadienyl group.

Preferable examples of cycloalkyl group include C₃₋₁₀ cycloalkyl groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicycle[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicycle[3.3.1]nonyl,bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.

Preferable examples of the cycloalkenyl group include C₃₋₁₀ cycloalkenylgroups such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yland 3-cyclohexen-1-yl.

Preferable examples of the cycloalkadienyl group include C₄₋₁₀cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl.

Preferable examples of the aryl group include C₆₋₁₄ aryl groups such asphenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl, phenanthryl andacenaphthylenyl.

Preferable examples of the aromatic heterocyclic group include aromaticmonocyclic heterocyclic groups such as furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensedheterocyclic groups such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,β-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and1,2,4-triazolo(4,3-b)pyridazinyl.

Preferable examples of the non-aromatic heterocyclic group includeoxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpholino andthiomorpholino.

Examples of the halogen atom include fluorine, chlorine, bromine andiodine.

As the substituted amino group in the optionally substituted aminogroup, mention is made of, N-monosubstituted amino group andN,N-disubstituted amino group. Examples of the substituted amino groupsinclude amino groups having one or two substituents selected from C₁₋₁₀alkyl group, C₂₋₁₀ alkenyl group, C₂₋₁₀ alkynyl group, aromatic group,heterocyclic group and C₁₋₁₀ acyl group (e.g. methylamino,dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino,cyclohexylamino, phenylamino, N-methyl-N-phenyl-amino, acetylamino,propionylamino, benzoylamino and nicotinoylamino).

As the acyl group, mention is made of C₁₋₁₃ acyl groups such as C₁₋₁₀alkanoyl group, C₃₋₁₀ alkenoyl group, C₄₋₁₀ cycloalkanoyl group, C₄₋₁₀cycloalkenoyl group and C₆₋₁₂ aromatic carbonyl group.

Preferable examples of the C₁₋₁₀ alkanoyl group include formyl acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,heptanoyl and octanoyl. Preferable examples of the C₃₋₁₀ alkenoyl groupinclude acryloyl, methacryloyl, crotonoyl and isocrotonoyl. Preferableexamples of C₄₋₁₀ cycloalkanoyl group include cyclobutanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl and cycloheptanecarbonyl.Preferable examples of C₄₋₁₀ cycloalkenoyl group include2-cyclohexenecarbonyl. Preferable examples of C₆₋₁₂ aromatic carbonylgroup include benzoyl, naphthoyl and nicotinoyl.

As the substituent in the substituted acyl group, mention is made of,for example, C₁₋₃ alkyl group, C₁₋₃ alkoxy group, halogen atom (e.g.chlorine, fluorine, bromine, etc.), nitro group, hydroxyl group andamino group.

As the substituted hydroxyl group in the optionally substituted hydroxylgroup, mention is made of, for example, alkoxy group, cycloalkyloxygroup, alkenyloxy group, cycloalkenyloxy group, aralkyloxy group,acyloxy group and aryloxy group.

Preferable examples of the alkoxy group include C₁₋₁₀ alkoxy groups suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy,t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxyand nonyloxy. Preferable examples of the cycloalkyloxy group includeC₃₋₁₀ cycloalkyloxy groups such as cyclobutoxy, cyclopentyloxy andcyclohexyloxy. Preferable examples of the alkenyloxy group include C₂₋₁₀alkenyloxy groups such as allyloxy, crotyloxy, 2-pentenyloxy and3-hexenyloxy. Preferable examples of the cycloalkenyloxy group includeC₃₋₁₀ cycloalkenyloxy groups such as 2-cyclopentenyloxy and2-cyclohexenyloxy. Preferable examples of the aralkyloxy group includeC₇₋₁₀ aryloxy groups such as phenyl-C₁₋₁₀, alkyloxy (e.g. benzyloxy andphenethyloxy). Preferable examples of the acyloxy group include C₂₋₁₃acyloxy group, more preferably C₂₋₄ alkanoyloxy groups (e.g. acetyloxy,propionyloxy, butyryloxy and isobutyryloxy). Preferable examples of thearyloxy group include C₆₋₁₄ aryloxy groups such as phenoxy andnaphthyloxy. The aryloxy group may optionally have one or twosubstituents such as halogen atom (e.g. chlorine, fluorine, bromine).Examples of the -substituted aryloxy group include 4-chlorophenoxy.

As the substituted thiol group in the optionally substituted thiolgroup, mention is made of, alkylthio group, cycloalkylthio group,alkenylthio group, cycloalkenylthio group, aralkylthio group, acylthiogroup and arylthio group.

Preferable examples of the alkylthio group include C₁₋₁₀ alkylthiogroups such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio,isopentylthio, neopentylthio, hexylthio, heptylthio and nonylthio.Preferable examples of the cycloalkylthio group include C₃₋₁₀cycloalkylthio groups such as cyclobutylthio, cyclopentylthio andcyclohexylthio. Preferable examples of the alkenylthio group includeC₂₋₁₀ alkenylthio groups such as allylthio, crotylthio, 2-pentenylthioand 3-hexenylthio. Preferable examples of the cycloalkenylthio groupinclude C₃₋₁₀ cycloalkenylthio groups such as 2-cyclopentenylthio and2-cyclohexenylthio. Preferable examples of the aralkylthio include C₇₋₁₀aralkylthio groups such as phenyl-C₁₋₄ alkylthio (e.g—benzylthio andphenethylthio). Preferable examples of the acylthio group include C₂₋₁₃acylthio group, more preferably C₂₋₄ alkanoylthio groups (e.g.acetylthio, propionylthio, butyrylthio and isobutyrylthio).

Preferable examples of the arylthio group include C₆₋₁₄ arylthio groupssuch as phenylthio and naphthylthio. The arylthio group may optionallyhave one or two substituents such as halogen atom (e.g. chlorine,fluorine, bromine). Examples of the substituted arylthio group include4-chlorophenylthio.

As the optionally esterified carboxyl group, mention is made of, forexample, alkoxycarbonyl group, aralkyloxycarbonyl group andaryloxycarbonyl group.

Preferable examples of the alkoxycarbonyl group include C₂₋₅alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and butoxycarbonyl. Preferable examples of thearalkyloxycarbonyl group include C₈₋₁₀ aralkyloxycarbonyl groups such asbenzyloxycarbonyl. Preferable examples of the aryloxycarbonyl groupinclude C₇₋₁₅ aryloxycarbonyl groups such as phenoxycarbonyl andp-tolyloxycarbonyl.

Among the substituents on the hydrocarbon group and heterocyclic grouprepresented by R, C₁₋₁₀ alkyl groups, aromatic heterocyclic groups andC₆₋₁₄ aryl groups are preferable, and C₁₋₃ alkyl, furyl, thienyl, phenyland naphthyl are especially preferable.

In the formula (I), substituents on the hydrocarbon group andheterocyclic group which are represented by R, may, when they arealicyclic hydrocarbon group, aryl group, aromatic heterocyclic group ornon-aromatic heterocyclic group, have one or more, preferably 1 to 3, ofsuitable substituents respectively. Examples of these substituentsinclude C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₂₋₆ alkynyl groups,C₃₋₇ cycloalkyl groups, C₆₋₁₄ aryl groups, aromatic heterocyclic groups(e.g. thienyl, furyl, pyridyl, oxazolyl and thiazolyl), non-aromaticheterocyclic groups (e.g. tetrahydrofuryl, morpholino, thiomorpholino,piperidino, pyrrolidino and piperazino), C₇₋₉ aralkyl groups, aminogroup, N-mono-C₁₋₄ alkylamino groups, N,N-di-C₁₋₄ alkylamino groups,C₂₋₈ acylamino groups (e.g. acetylamino, propionylamino andbonzoylamino), amidino group, C₂₋₈ acyl group (e.g. C₂₋₈ alkanoylgroups), carbamoyl group, N-mono-C₁₋₄ alkyl carbamoyl groups,N,N-di-C₁₋₄ alkyl carbamoyl groups, sulfamoyl group, N-mono-C₁₋₄ alkylsulfamoyl groups, N,N-di-C₁₋₄ alkyl sulfamoyl groups, carboxyl group,C₂₋₈ alkoxycarbonyl groups, hydroxyl group, C₁₋₄ alkoxy groups, C₂₋₅alkenyloxy groups, C₃₋₇ cycloalkyloxy groups, C₇₋₉ aralkyloxy groups,C₆₋₁₄ aryloxy groups, mercapto group, C₁₋₄ alkylthio groups, C₆₋₁₄arylthio groups sulfo group, cyano group, azido group, nitro group,nitroso group and halogen atom.

In the formula (I), R is preferably an optionally substitutedheterocyclic group. R is more preferably pyridyl, okazolyl or thiazolylgroup which is optionally substituted by 1 to 3 substituents selectedfrom C₁₋₃ alkyl group, furyl group, thienyl group, phenyl group andnaphthyl group.

R′ in the formula (II) has the same definition as R except that R′ doesnot represent benzopyranyl group when m and n are 0; X represents CH; Arepresents a bond; Q represents sulfur atom; R¹, L and M representhydrogen atom; and ring E does not have further substituents.

In the formulae (I) and (II), Y represents —CO—, —CH(OH)— or —NR³—(wherein R³ represents an optionally substituted alkyl group),preferably —CH(OH)— or —NR³—. As the alkyl group in the optionallysubstituted alkyl group represented by R³, mention is made of, forexample, C₁₋₄ alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec.-butyl and t.-butyl. Examples of the substituentsinclude halogen (e.g., fluorine, chlorine, bromine and iodine), C₁₋₄alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy,sec.-butoxy and t.-butoxy), hydroxyl group, nitro group and C₁₋₄ acylgroups (e.g. formyl, acetyl and propionyl).

The symbol m is 0 or 1, preferably 0.

The symbol n is 0, 1 or 2, preferably 0 or 1.

X represents CH or N, preferably CH.

In the formulae (I) and (II), A represents a bond or a C₁₋₇ divalentaliphatic hydrocarbon group. The aliphatic hydrocarbon group may bestraight-chain or branched, and saturated or unsaturated. Specificexamples of the aliphatic hydrocarbon group include saturated ones [e.g.—CH₂—, —CH(CH₃)—, —(CH₂)₂—, —CH(C₂H₅)—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₆— and —(CH₂)₇—] and unsaturated ones [e.g. —CH═CH—, —C(CH₃)═CH—,—CH═CH—CH₂—, —C(C₂H₅)═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—CH₂—.—CH═CH—CH═CH—CH₂— and —CH═CH—CH═CH—CH═CH—CH₂—. A is preferably a bond orC₁₋₄ divalent aliphatic hydrocarbon groups, the aliphatic hydrocarbongroups preferably being saturated. A is more preferably a bond or—(CH₂)₂

As the alkyl group represented by R¹, substantially the same one as thealkyl group in the above-mentioned R³. R¹ is preferably hydrogen atom.

In the formulae (I) and (II), the partial formula:

Ring E has 1 to 4 substituents at any substitutable positions. Examplesof such substituents include alkyl group, optionally substitutedhydroxyl group, halogen atom, optionally substituted acyl group andoptionally substituted amino group. These substituents havesubstantially the same meaning as those described as substituents of thehydrocarbon group and heterocyclic group represented by R.

Ring E, namely the partial formula:

wherein R² represents hydrogen atom, an alkyl group, an optionallysubstituted hydroxyl group, a halogen atom, an optionally substitutedacyl group, nitro group or an optionally substituted amino group.

As the alkyl group, optionally substituted hydroxyl group, halogen atom,optionally substituted acyl group and optionally substituted amino grouprepresented by R², mention is made of those described as substituents ofthe hydrocarbon group and heterocyclic group represented by R. R² ispreferably hydrogen atom, optionally substituted hydroxyl group orhalogen atom, more preferably hydrogen atom or optionally substitutedhydroxyl group, especially preferably hydrogen atom or C₁₋₄ alkoxygroups.

In the formulae (I) and (II), L and N represent hydrogen atom, or theymay optionally be combined with each other to form a bond. L and M arepreferably hydrogen atom.

In the compounds wherein L and M are combined with each other to form abond, there exist (E) and (Z)-isomers relative to the double bond at the5-position of the azolidinedione ring.

And, in the compounds wherein L and M respectively represent hydrogenatom, there exist (R)- and (S)-optical isomers due to the asymmetriccarbon at the 5-position of the azolidinedione ring. The compoundsinclude these (R)- and (S)-optical isomers and racemic isomers.

Preferable examples of the compounds represented by the formula (I) or(II) includes those in which R is pyridyl, oxazolyl or thiazolyl groupoptionally having 1 to 3 substituents selected from C₁₋₃ alkyl, furyl,thienyl, phenyl and naphthyl; m is 0; n is 0 or 1; X is CH; A is a bondor —(CH₂)₂—; R¹ is hydrogen atom; ring E, namely the partial formula:

and R² is hydrogen atom or C₁₋₄ alkoxy group; and L and M are bothhydrogen atom.

Preferable examples of the compound represented by the formula (I)include

(1) the compound represented by the formula (III) such as5-[4-[2-(3-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione;5-[4-[2-(4-ethyl-2-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione;5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (genericname: pioglitazone); and5-[4-[2-(6-ethyl-2-pyridyl)-ethoxy]benzyl]-2,4-thiazolidinedione;

(2)(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)-3-methoxyphenyl]propyl]-2,4-oxazolidinedione;and

(3)5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(generic name: troglitazome/CS-045).

The compound represented by the formula (I) is especially preferablypioglitazone.

The compound represented by the formula (II) is preferably the compoundrepresented by the formula (III) and(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)-3-methoxyphenyl]propyl]-2,4-oxazolidinedione,more preferably pioglitazone.

The pharmacologically acceptable salt of the compound represented by theformula (I) or (II) are exemplified by salts with inorganic bases, saltswith organic bases, salts with inorganic acids, salts with organicacids, and salts with basic or acidic amino acids.

Preferable examples of salts with inorganic bases include salts withalkali metals such as sodium, potassium, etc., salts with alkaline earthmetals such as calcium, magnesium, etc., and salts with aluminum,ammonium, etc.

Preferable examples of salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, etc.

Preferable examples of salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc.

Preferable examples of salts with organic acids include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric, acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.

Preferable examples of salts with basic amino acids include salts witharginine, lysine, ornithine, etc., and preferable examples of salts withacidic amino acids include salts with aspartic acid, glutamic acid, etc.

The pharmacologically acceptable salt of the compound represented by theformula (III) is preferably a salt with an inorganic acid, morepreferably a salt with hydrochloric acid. Especially, pioglitazone ispreferably used in the form of salt with hydrochloric acid.

The compounds represented by the formula (I) or (II) or a salt thereofcan be produced in accordance with, for example, methods described inJPA S55 (1980)-22636(EP-A 8203), JPA S60 (1985)-208980 (EP-A 155845),JPA S61 (1986)-286376 (EP-A 208420), JPA S61 (1986)-85372 (EP-A 177353),JPA S61 (1986)-267580 (EP-A 193256), JPA H5 (1993)-86057 (WO 92/18501),JPA H7 (1995)-82269 (EP-A 605228), JPA H7 (1995)-101945 (EP-A 612743),EP-A 643050, EP-A 710659, etc. or methods analogous thereto.

Insulin sensitivity enhancers include5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl]methyl]-2,4-thiazolidinedione(generic name: englitazone) or its sodium salt;5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thiazolidinedione(generic name: darglitazone/CP-86325) or its sodium salt;5-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-ylmethyl]-2,4-oxazolidinedione(CP-92768); 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31637);4-[(2-naphthalenyl)methyl]-3H-1,2,3,5-oxathiadiazol-2-oxide (AY-30711);and 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]pheny]-methyl];2,4-thiazolidinedione (BRL-49653), etc. in addition to compoundsmentioned hereinbefore.

In the present invention, examples of the drug which is used incombination with the above-mentioned insulin sensitivity enhancerinclude an α-glucosidase inhibitor, an aldose reductase inhibitor, abiguanide, a statin compound, a squalene synthesis inhibitor, a fibratecompound, a LDL catabolism enhancer and an angiotensin converting enzymeinhibitor.

α-Glucosidase inhibitors are drugs which inhibit digestive enzymes suchas amylase, maltase, α-dextrinase, sucrase, etc. to retard digestion ofstarch and sugars. Examples of the α-glucosidase inhibitors includeacarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (generic name;voglibose), miglitol, etc. with preference given to voglibose.

Aldose reductase inhibitors are drugs which inhibit the first-stagerate-limitting enzyme in the polyol pathway to prevent or arrestdiabetic complications. In the hyperglycemic state of diabetes, theutilization of glucose in the polyol pathway is increased and the excesssorbitol accumulated intracellularly as a consequence acts as a tissuetoxin and hence evokes the onset of complications such as diabeticneuropathy, retinopathy, and nephropathy. Examples of the aldosereductase inhibitors include tolurestat; epalrestat;3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid;2,7-difluoro-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione (genericname: imirestat);3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (generic name: zenarestat);6-fluoro-2,3-dihydro-2′,5′-dioxo-spiro[4H-1-benzopyran-4,4′-imidazolidine]-2-carboxamide(SNK-860); zopolrestat; sorbinil;1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M−16209),etc.

Biguanides are drugs having actions of stimulation of anaerobicglycolysis, increase of the sensitivity to insulin in the peripheraltissues, inhibition of glucose absorption from the intestine,suppression of hepatic gluconeogenesis, and inhibition of fatty acidoxidation. Examples of the biguanides include phenformin, metformin,buformin etc.

Statin compounds are drugs having actions of lowering blood cholesterollevels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase.Examples of the statin compounds include pravastatin and its sodiumsalt, simvastatin, lovastatin, atorvastatin, fluvastatin, etc.

Squalene synthesis inhibitors are drugs having actions of lowering bloodcholesterol levels by inhibiting synthesis of squalene. Examples of thesqualene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, mono potassium salt (BMS-188494).

Fibrate compounds are drugs having actions of lowering blood cholesterollevels by inhibiting synthesis and secretion of triglycerides in liverand activating a lipoprotein lipase.

Examples of the fibrate compounds include bezafibrate, beclobrate,binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid,etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate,ronifibrate, simfibrate, theofibrate, etc.

LDL catabolism enhancers are drugs having actions of lowering bloodcholesterol levels by increasing the number of LDL (low-densitylipoprotein) receptors.

Examples of the LDL catabolism enhancers include the compound which isdescribed in JPA 117 (1995)-316144 and represented by the formula:

wherein R⁴, R⁵, R⁶ and R⁷ are the same or different, and representhydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxygroup; r is 0-2; s is 2-4; p is 1-2; or a salt thereof; specificallyN-[2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienicacid amide, etc.

The above-mentioned statin compounds, squalene synthesis inhibitors,fibrate compounds and LDL catabolism enhancers can be substituted withother drugs having the property to lower blood cholesterol andtriglyceride levels. Examples of these drugs include nicotinic acidderivatives such as nicomol and niceritrol; antioxidants such asprobucol; and ion-exchange resins such as colestyramin.

Angiotensin converting enzyme inhibitors are drugs having actions ofpartially lowering blood glucose levels as well as lowering bloodpressure by inhibiting angiotensin converting enzymes. Examples of theangiotensin converting enzyme inhibitors include captopril, enalapril,alacepril, delapril, ramipril, lisinopril, imidapril, benazepril,ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril,perindopril, quinapril, spirapril, temocapril, trandolapril, etc.

In the present invention, especially preferred is the pharmaceuticalcomposition which comprises an insulin sensitivity enhancer incombination with an α-glucosidase inhibitor. The insulin sensitivityenhancer is especially preferably pioglitazone, and the α-glucosidaseinhibitor is especially preferably voglibose.

In the present invention, examples of the drug which is used incombination with the compound represented by the formula (II) or apharmacologically acceptable salt thereof include an insulin secretionenhancer and/or an insulin preparation.

Insulin secretion enhancers are drugs having the property to promotesecretion of insulin from pancreatic β cells. Examples of the insulinsecretion enhancers include sulfonylureas (SU). The sulfonylureas (SU)are drugs which promote secretion of insulin from pancreatic β cells bytransmitting signals of insulin secretion via SU receptors in the cellmembranes. Examples of the SU include -tolbutamide; chlorpropamide;tolazamide; acetohexamide;4-chloro-N-[(1-pyrrolidinylamino)carbonyl)-benzenesulfonamide (genericname: glycopyramide) or its ammonium salt; glibenclamide (glyburide);gliclazide; 1-butyl-3-metanilylurea; carbutamide; glibonuride;glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole;glyhexamide; glymidine; glypinamide; phenbutamide; tolcyclamide, etc.

Insulin secretion enhancers includeN-[[4-(1-methylethyl)cyclohexyl)carbonyl]-D-phenylalanine (AY-4166);calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionatedihydrate (KAP-1229); and glimepiride (Hoe 490), etc. in addition tocompounds mentioned hereinbefore. The insulin secretion enhancer isespecially preferably glibenclamide.

Examples of the insulin preparations include animal insulin preparationstypically extracted from bovine or porcine pancreas and human insulin,preparations synthesized by genetic engineering techniques typicallyusing Escherichia coli or yeasts. While insulin preparations areavailable in a variety of types, e.g. immediate-acting, bimodal-acting,intermediate-acting, and long-acting, these types of preparations can beselectively administered according to the patient's condition.

In the present invention, especially preferred is the pharmaceuticalcomposition which comprises the compound represented by the formula (II)or a pharmacologically acceptable salt thereof in combination with aninsulin secretion enhancer. The compound represented by the formula (II)or a pharmacologically acceptable salt thereof is especially preferablypioglitazone, and the insulin secretion enhancer is especiallypreferably glibenclamide.

The pharmaceutical composition comprising an insulin sensitivityenhancer in combination with at least one member selected from the groupconsisting of an α-glucosidase inhibitor, an aldose reductase inhibitor,a biguanide, a statin compound, a squalene synthesis inhibitor, afibrate compound, a LDL catabolism enhancer and an angiotensinconverting enzyme inhibitor; and the pharmaceutical compositioncomprising the compound represented by the formula (II) or apharmacologically acceptable salt thereof in combination with an insulinsecretion enhancer and/or an insulin preparation, both provided inaccordance with the present invention, can be respectively put to use bymixing the respective active components either all together orindependently with a physiologically acceptable carrier, excipient,binder, diluent, etc. and administering the mixture or mixtures eitherorally or non-orally as a pharmaceutical composition. When the activecomponents are formulated independently, the respective formulations canbe extemporaneously admixed using a diluent or the like and administeredor can be administered independently of each other, either concurrentlyor at staggered times to the same subject.

The dosage form for said pharmaceutical composition includes such oraldosage forms as granules, powders, tablets, capsules, syrups, emulsions,suspensions, etc. and such non-oral dosage forms as injections (e.g.subcutaneous, intravenous, intramuscular and intraperitonealinjections), drip infusions, external application forms (e.g. nasalspray preparations, transdermal preparations; ointments, etc.), andsuppositories (e.g. rectal and vaginal suppositories).

These dosage forms can be manufactured by the per se known techniqueconventionally used in pharmaceutical procedures. The specificmanufacturing procedures are as follows.

To manufacture an oral dosage form, an excipient (e.g. lactose, sucrose,starch, mannitol, etc.), a disintegrator (e.g. calcium carbonate,carboxymethylcellulose calcium, etc.), a binder (e.g. α-starch, gumarabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, etc.), and a lubricant (e.g. talc, magnesiumstearate, polyethylene glycol 6000, etc.), for instance, are added tothe active component or components and the resulting composition iscompressed. Where necessary, the compressed product is coated, by theper se known technique, for masking the taste or for enteric dissolutionor sustained release. The coating material that can be used includes,for instance, ethyl-cellulose, hydroxymethylcellulose, polyoxyethyleneglycol, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, and Eudragit (Rohm & Haas, Germany; methacrylic-acryliccopolymer).

Injections can be manufactured typical]s by the following procedure. Theactive component or components are dissolved, suspended or emulsified inaqueous vehicle (e.g. distilled water, physiological saline, Ringer'ssolution, etc.) or an oily vehicle (e.g. vegetable oil such as oliveoil, sesame oil, cottonseed oil, corn oil, etc. or propylene glycol)together with a dispersant (e.g. Tween 80 (Atlas Powder, U.S.A.), HCO 60(Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodiumalginate, etc.), a preservative (e.g. methyl p-hydroxybenzoate, propylp-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), anisotonizing agent (e.g. sodium chloride, glycerol, sorbitol, glucose,inverted sugar, etc.) and other additives. If desired, a solubilizer(e.g. sodium salicylate, sodium acetate, etc.), a stabilizer (e.g. humanserum albumin), a soothing agent (e.g. benzalkonium chloride, procainehydrochloride, etc.) and other additives can also be added.

A dosage form for external application can be manufactured by processingthe active component or components into a solid, semi-solid or liquidcomposition. To manufacture a solid composition, for instance, theactive component or components, either as they are or in admixture withan excipient (e.g. lactose, mannitol, starch, microcrystallinecellulose, sucrose, etc.), a thickener (e.g. natural gums, cellulosederivatives, acrylic polymers, etc.), etc., are processed into powders.The liquid composition can be manufactured in substantially the samemanner as the injections mentioned above. The semi-solid composition ispreferably provided in a hydrous or oily gel form or an ointment form.These compositions may optionally contain a pH control agent (e.g.carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodiumhydroxide, etc.), and a preservative (e.g. p-hydroxybenzoic acid esters,chlorobutanol, benzalkonium chloride, etc.), among other additives.

Suppositories can be manufactured by processing the active component orcomponents into an oily or aqueous composition, whether solid,semi-solid or liquid. The oleaginous base that can be used includes, forinstance, higher fatty acid glycerides [e.g. cacao butter, Witepsols(Dinamit-Nobel), etc.], medium-chain fatty acids [e.g. Migriols(Dinamit-Nobel), etc.], vegetable oils (e.g. sesame oil, soybean oil,cottonseed oil, etc.), etc. The water-soluble base includes, forinstance, polyethylene glycols, propylene. glycol, etc. The hydrophilicbase includes, for instance, natural gums, cellulose derivatives, vinylpolymers, and acrylic polymers, etc.

The pharmaceutical composition of the present invention is low intoxicity and can be safely used in mammals (e.g. humans, mice, rats,rabbits, dogs, cats, bovines, horses, swine, monkeys).

The dosage of the pharmaceutical composition of the present inventionmay be appropriately determined with reference to the dosagesrecommended for the respective active components and can be selectedappropriately according to the recipient, the recipient's age and bodyweight, current clinical status, administration time, dosage form,method of administration, and combination of the active components,among other factors. For example, the dosage of the insulin sensitivityenhancer for an adult can be selected from the clinical oral dose range0.01 to 10 mg/kg body weight (preferably 0.05 to 10 mg/kg body weight,more preferably 0.05 to 5 mg/kg body weight) or the clinical parenteraldose range of 0.005 to 10 mg/kg body weight (preferably 0.01 to 10 mg/kgbody weight, more preferably 0.01 to 1 mg/kg body weight). The otheractive component or components having different modes of action for usein combination can also be used in dose ranges selected by referring tothe respective recommended clinical dose ranges. The preferred frequencyof administration is 1 to 3 times a day.

The proportions of the active components in the pharmaceuticalcomposition of the present invention can be appropriately selectedaccording to the recipient, the recipient's age and body weight, currentclinical status, administration time, dosage form, method ofadministration, and combination of active components, among otherfactors. When, for example, the compound represented by the formula (I)or a pharmacologically acceptable sale thereof (e.g. pioglitazone) whichis the insulin sensitivity enhancer and voglibose which is anα-glucosidase inhibitor are to be administered in combination to a humansubject, voglibose is used in a proportion of usually about 0.0001 to0.2 weight parts and preferably about 0.001 to 0.02 weight partsrelative to 1 weight part of the compound or a salt thereof. When, forexample, the compound represented by the formula (II) or apharmacologically acceptable salt thereof and glibenclamide which is aninsulin secretion enhancer are to be administered in combination to ahuman subject, glibenclamide is used in a proportion of usually about0.002 to 5 weight parts and preferably about 0.025 to 0.5 weight parts,relative to 1 weight part of the compound or a pharmacologicallyacceptable salt thereof.

The pharmaceutical composition of the present invention shows a markedsynergistic effect compared with administration of either activecomponent alone. For example, compared with cases in which each of theseactive components was administered to diabetic Wistar fatty rats withgenetic obesity, administration of these active components incombination resulted in marked improvements in both hyperglycemia andreduced glucose tolerance. Thus, the pharmaceutical composition of thepresent invention lowers blood glucose in diabetics more effectivelythan it is the case with administration of each component drug aloneand, therefore, can be used advantageously for the prophylaxis andtreatment of diabetic complications.

Furthermore, since the pharmaceutical composition of the presentinvention develops sufficient efficacy with reduced doses as comparedwith the administration of any one of the active components alone, theside effects of the respective components (e.g. gastrointestinaldisorders such as diarrhea, etc.) can be reduced.

The following working examples and experimental examples are merelyintended to illustrate the present invention in further detail butshould by no means be construed as defining the scope of the invention.

The pharmaceutical composition of the present invention can be preparedaccording to the following formulations.

Working Example 1 Capsules

(1) Pioglitazone hydrochloride 30 mg (2) Voglibose 0.2 mg (3) Lactose 60mg (4) Microcrystalline cellulose 79.8 mg (5) Magnesium stearate 10 mgTotal 180 mg

The whole amounts of (1), (2), (3) and (4) and half the amount of (5)are mixed well and granulated in the conventional manner. Then, thebalance of (5) is added and, after mixing, the whole composition isfilled in a gelatin hard capsule shell.

Working Example 1 Capsules

(1) Pioglitazone hydrochloride 10 mg (2) Glibenclamide 1.25 mg (3)Lactose 86.25 mg (4) Corn starch 20 mg (5) Polyethylene glycol 2.5 mg(6) Hydroxypropylcellulose 4 mg (7) Carmellose calcium 5.5 mg (8)Magnesium stearate 0.5 mg Total 130 mg (per tablet)

The whole amounts of (1), (2), (3), (4), and (5), ⅔ amounts of (6) and(7), and ½ amount of (8) are mixed well and granulated in theconventional manner. Then, the balances of (6), (7) and (8) are added tothe granules, which is mixed well and the whole composition iscompressed with a tablet machine. The adult dosage is 3 tablets/day, tobe taken in 1 to 3 divided doses.

Working Example 3 Capsules

(1) Pioglitazone hydrochloride 10 mg (2) Epalrestat 50 mg (3) Lactose 55mg (4) Microcrystalline cellulose 55 mg (5) Magnesium stearate 10 mgTotal 180 mg 

The whole amounts of (1), (2), (3) and (4) and ½ amount of (5) are mixedwell and granulated in the conventional manner. Then, the balance of (5)is added and the whole composition is filled in gelatin capsule shell.The adult dosage is 3 capsules/day, to be taken in 1 to 3 divided doses.

Experimental Example 1

Effect of pioglitazone hydrochloride in combination with α-glucosidaseinhibitor in genetically obese and diabetic Wistar fatty rats.

Male Wistar fatty rats aged 14-19 weeks were divided into 4 groups of5-6, and pioglitazone hydrochloride (1 mg/kg body wt./day, p.o.) and/orvoglibose (an α-glucosidase inhibitor) (0.31 mg/kg body wt./day;administered by mixing in commercial diet at a rate of 5 ppm) wasadministered for 14 days. The blood was then collected from the tailvein and the plasma glucose and hemoglobin A₁ were determined by theenzymatic method (Encore Chemical System, Baker) and using a commercialkit (NC-ROPET, Nippon Chemiphar Co.), respectively. The results wereexpressed in mean±standard deviation for each group (n=5-6) and analyzedby Dunnett's test, which are shown in Table 1. The 1% level ofsignificance was used.

TABLE 1 Plasma glucose Hemoglobin A₁ Group (mg/dl) (%) Control 345 ± 295.7 ± 0.4 Pioglitazone  215 ± 50* 5.2 ± 0.3 Voglibose 326 ± 46 6.0 ± 0.6Pioglitazone + voglibose  114 ± 23*  4.5 ± 0.4* *P < 0.01 vs. controlgroup

It is apparent: from Table 1 that both the blood glucose and hemoglobinA₁ levels were remarkably lowered by combined administration ofpioglitazone and voglibose as compared with the administration of eitherdrug alone.

Experimental Example 2

Effect of pioglitazone hydrochloride in combination with an insulinsecretion enhancer in genetically obese and diabetic Wistar fatty rats.

Male Wistar fatty rats aged 13-14 weeks were divided into 4 groups of 5,and pioglitazone hydrochloride (3 mg/kg/day, p.o.) and/or glibenclamide(an insulin secretion enhancer) (3 mg/kg/day, p.o.) was administered for7 days. Following an overnight fast, the oral glucose loading test (2 gglucose/kg/5 ml, p.o.) was carried out. Prior to glucose loading and 120and 240 minutes after the loading, blood was collected from the tailvein and the plasma glucose was assayed by the enzymatic method (EncoreChemical System, Baker). The results were expressed in mean±SD for eachgroup (n=5) and analyzed by Dunnett's test, which are shown in Table 2.

TABLE 2 Plasma glucose (mg/dl) — Group 0 min. 120 min. 240 min. Control119 ± 9  241 ± 58  137 ± 10 Pioglitazone 102 ± 12 136 ± 17* 102 ± 9*Glibenclamide 118 ± 12 222 ± 61   106 ± 24* Pioglitazone + Glibenclamide108 ± 3   86 ± 10*  6.0 ± 5* *P < 0.01 vs. control group

It is apparent from Table 2 that the increase of blood sugar followingglucose loading was remarkably inhibited by the combined administrationof pioglitazone and glibenclamide as compared with the administration ofeither drug alone.

The pharmaceutical composition of the present invention shows a potentdepressive effect on diabetic hyperglycemia and is useful forprophylaxis and treatment of diabetes. Moreover, this pharmaceuticalcomposition is useful for prophylaxis and treatment of diabeticcomplications such as diabetic neuropathy, nephropathy, retinopathy,macroangiopathy, and osteopenia. In addition, by appropriately selectingthe kinds of component drugs, administration route, dosage, etc.according to clinical status, stable hypoglycemic efficacy in long-termtherapy can be expected with an extremely low risk of side effect.

1.-22. (canceled)
 23. A method for manufacturing a pharmaceuticalcomposition, comprising forming an admixture comprising an insulinsensitivity enhancer and a biguanide, wherein the insulin sensitivityenhancer is selected from the group consisting of: (a)5-[4-[2-(3-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione or itspharmacologically acceptable salt, (b)5-[4-[2-(4-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione or itspharmacologically acceptable salt, (c)5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione or itspharmacologically acceptable salt, (d)5-[4-[2-(6-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione or itspharmacologically acceptable salt, (e)(R)-(+)-5-[3-[4-(2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedioneor its pharmacologically acceptable salt, (f)5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl]methyl]-2,4-thiazolidinedioneor its sodium salt, (g)5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thiazolidinedione or its sodium salt, (h)5-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-ylmethyl]-2,4-oxazolidinedione,(i) 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione, and (j)5-[[4-(2-methyl-2-pyridylamino)ethoxy)phenyl]methyl]-2,4-thiazolidinedioneor its pharmacologically acceptable salt.
 24. The method of claim 23,wherein the admixture further comprises an excipient, a disintegrator, abinder, and a lubricant.
 25. The method of claim 23, wherein theadmixture further comprises an excipient and a thickener.
 26. The methodof claim 23, further comprising compressing the admixture.
 27. Themethod of claim 26, further comprising applying a coating to thecompressed admixture.
 28. The method of claim 27, wherein the coatingcomprises a material selected from the group consisting of (a)ethyl-cellulose, (b) hydroxymethylcellulose, (c) polyoxyethylene glycol,(d) cellulose acetate phthalate, (e) hydroxypropylmethylcellulosephthalate, and (f) a methacrylic-acrylic copolymer.
 29. The method ofclaim 23, wherein the admixture is a powder.
 30. The method of claim 23,wherein the admixture is a liquid.
 31. The method of claim 23, whereinthe admixture is a semi-solid.
 32. The method of claim 23, wherein theadmixture further comprises an oleaginous base, a water-soluble base, ora hydrophilic base.
 33. The method of claim 23, wherein the admixturefurther comprises an aqueous vehicle or an oily vehicle, and wherein theinsulin sensitivity enhancer and biguanide are dissolved, suspended, oremulsified in the aqueous vehicle or the oily vehicle.
 34. The method ofclaim 33, wherein the admixture further comprises a dispersant.
 35. Themethod of claim 34, wherein the admixture further comprises apreservative.
 36. The method of claim 23, wherein the insulinsensitivity enhancer is pioglitazone or its hydrochloride.
 37. Themethod of claim 23, wherein the biguanide is selected from the groupconsisting of phenformin, metformin, and buformin.
 38. The method ofclaim 23, wherein the insulin sensitivity enhancer is pioglitazone orits hydrochloride and the biguanide is metformin.
 39. A method formanufacturing an oral dosage form, comprising (a) forming an admixturecomprising an insulin sensitivity enhancer, biguanide, and an excipient,wherein the insulin sensitivity enhancer is pioglitazone hydrochlorideand the biguanide is metformin; (b) compressing the admixture; and (c)coating the compressed admixture to form an oral dosage form.
 40. Themethod of claim 39, wherein the admixture further comprises polyethyleneglycol, magnesium stearate, and talc.